The non-communicable disease, diabetes mellitus, can be divided into two major types, viz. type 1 diabetes (T1 D) and type 2 diabetes (T2D). T1 D is characterized by β-cell autoimmunity. In T2D, the pancreatic β-cells produce insufficient insulin, and the peripheral tissues (liver, muscle and adipose tissue) are “resistant” to actions of insulin, i.e. glucose uptake is inefficient in these target tissues. The β-cells are also often destroyed in late stages of T2D making the patient dependant on insulin treatment. In diabetes patients, approximately 5-10% are type 1 and 90-95% are type 2 diabetic. Major diabetic complications include retinopathy, cerebrovascular disease, coronary heart disease, neuropathy, peripheral vascular disease, ulceration and amputation. Thus diabetes affects several organs and tissues throughout the body. Factors that contribute to the development of diabetes include ethnicity (where certain population groups have an increased incidence of T2D, particularly if they have migrated), obesity, a high fat diet, the intrauterine environment, insulin resistance and specific candidate genes.
The incidence of type 2 diabetes is increasing worldwide. Although genetic factors may play a role, life-style changes such as the adoption of a Western diet, high in fat, leads to obesity which can be a factor also contributing to the increase of this disease. Life-style factors, such as increased fat intake and reduced exercise, have been shown to be associated with obesity and insulin resistance (Lipman et al., 1972; Lovejoy and DiGirolamo, 1992). In rats, high fat feeding induces a state of insulin resistance associated with diminished insulin-stimulated glycolysis and glycogen synthesis (Kim et al., 2000). This disease is a result of the peripheral insulin-responsive tissues, such as muscle and adipose tissue, displaying a significant decrease in response to insulin resulting in an increase in circulating glucose and fatty acids in the blood. The low response to insulin results in a decrease in glycolysis which in turn initiates gluconeogenesis and glycogenolysis in the liver, both of which are “switched off” by insulin under normal conditions. Pancreatic β-cells are able to cope with the initial insulin resistant phase by producing an excess of insulin and increasing the amount of insulin secreted (Pirol et al., 2004). The resulting hyperinsulinaemia to maintain normoglycaemia eventually brings about cell dysfunction (Khan, 2003) leading to overt diabetes. It is evident that type 2 diabetes is dependent on insults occurring both at peripheral as well as the cellular level (Khan et al., 2000).
It is well established that insulin resistance and subsequent β-cell failure are major factors influencing the progression from normal glucose tolerance, through impaired glucose tolerance, to T2D. Lifestyle changes associated with the move from a rural to an urban area lead to an increase in obesity in urban black South Africans and this is associated with insulin resistance, which is another feature of T2D. To compensate for the insulin resistant state, β-cells produce more insulin and this leads to a higher demand on the already overworked β-cells which will result in β-cell exhaustion and ultimately β-cell failure.
There were an estimated 30M people with diabetes in the world in 1985. By 1995 the number had increased to 135M. The latest World Health Organization (WHO) estimate is that 300M people will have diabetes in 2025, an increase of 122%. This is in agreement with the International Diabetes Federation (IDF) estimation, in 2025, of 333M people with diabetes (6.3% prevalence), while 472M will be diagnosed with impaired glucose tolerance (IGT; 9% prevalence). There will be an estimated increase of 42% from 51M to 72M, for the developed world (where there is an increase in the incidence of overweight and obese individuals, increasing their risk for becoming diabetic) and an increase of 170% from 84M to 228M for developing countries (due to a myriad of factors including dietary changes, increased physical activity and rapid urbanization). Thus while diabetes was previously considered a western life style disease affecting people in the developed countries, current trends suggest that by 2025 over 75% of all people with diabetes will be in the developing world. Another contributing factor to the increased incidence of diabetes in the developing world is developmental programming. In many parts of the developing world, people are often exposed to a poor diet (undernutrition) in utero followed by overnutrition postnatally which has been shown to predispose individuals to developing T2D. Furthermore, a total of 1.1 billion people are currently overweight, and 320M people are obese (IDF). This emphasizes the huge global economic burden of obesity, and as obesity is a major risk factor for developing diabetes, this may potentially further exacerbate the already huge economic burden associated with diabetes.
Conservative estimates for South Africa, based on minimal data, predict an increase from 5.6M in 2000 to over 8M in 2010. The largest increase is most likely to be in the black populations due to urbanisation, since this is accompanied by lifestyle and dietary changes from a low fat to a high fat diet. Figures in 1998 showed urban black South Africans to have an escalating incidence of T2D with the age-adjusted prevalence approaching 8% (Levitt, 1993), almost double the figure of 4.2% published in 1974 (Joffe & Seftel). In 1996 data for the top twenty causes of deaths in South Africa (Bradshaw et al, 1996) revealed diabetes to be the 10th in males and 7th in females. However, complications of diabetes, such as ischaemic heart disease and other cardiovascular and kidney complications contribute significantly to the number of deaths and adjusted figures could place diabetes in the top three or four causes of death in South Africa. The incidence of T2D is greater than HIV in SA, thus T2D warrants national attention.
Diabetes is an expensive disease and, although information on the cost of treating diabetics in South Africa is not available, there are many indirect costs. These include a reduction in the quality of life, the ability to contribute to the community and the workforce and its effect on the economy. This is exacerbated by an increased cost to Medical Aid Schemes resulting in increased Medical Aid premiums. Diabetes also affects the economy directly. In the absence of diabetes related financial data in South Africa, published data from the UK show that with more than 1.5M adults in the UK currently diagnosed with diabetes and its complications, the total National Health Service (NHS) cost is £5.2 billion each year, which is 9% of the total NHS budget. In the USA, the estimated direct costs are US$ 44 billion and, with loss of productivity, this figure increased to US$ 98 billion. Similar figures are available for many other countries.
T2D is diagnosed by raised levels of plasma glucose. However, our previous research has shown that by the time blood glucose levels increase, serious damage has already occurred in the cardiovascular system and the pancreas. Following diagnosis of diabetes by raised blood glucose levels, therapies such as diet and exercise and/or available medication can result in a temporary improvement in plasma glucose levels but cannot halt the progression of the disease. The rate of failure of these therapies is associated with the rate of continuing β-cell decline. Current treatment involves insulin injection or stimulating insulin release and/or action by medication.
There are many theories for explaining the impairment of insulin production by the pancreas that leads to the diabetic condition. Reference is made to two papers: “Mechanisms of pancreatic beta-cell destruction in type I diabetes” by Nerup J, Mandrup-Poulsen T, Molvig J, Helqvist S, Wogensen L, Egeberg J. published in Diabetes Care. 1988; 11 Suppl 1:16-23; and the second entitled “Autoimmune Imbalance and Double Negative T Cells Associated with Resistant, Prone and Diabetic Animals”, Hosszufalusi, N., Chan, E., Granger, G., and Charles, M.; J Autoimmun, 5: 305-18 (1992). These papers show that inflammation of the pancreatic islets interrupts insulin production. Specifically, the insulin producing β-cells in the pancreatic islets are destroyed by immune attack. Such β-cell destruction is recognized as being due to attack by several types of immune cells including NK (natural killer) cells and double negative T-Lymphocytes.
Diabetes is considered to be insidious, since there is no known cure. Various treatments, however, have been used to ameliorate diabetes. For example, dietetic measures have been employed to balance the relative amounts of proteins, fats, and carbohydrates in a patient. Diabetes education and awareness programmes have also been implemented in several countries. In addition, diabetic conditions of moderate or severe intensity are treated by the administration of insulin. Also, prescription drugs such as “Glucoside” have been employed to rejuvenate impaired insulin production in adult onset diabetics. Other drugs are used to modulate the effectiveness of insulin. In any case, treatment of either juvenile or adult onset diabetes, has achieved only partial success. This is due to most agents targeting either improved beta-cell function or reducing insulin resistance, with the effect attenuating as the disease progressively worsens. Thus patients require the use (often daily) of a combination of agents to control the disease.
Biguanides, such as metformin, became available for treatment of type 2 diabetes in the late 1950s, and have been effective hypoglycaemic agents ever since (Vigneri and Goldfine, 1987). Little is known about the exact molecular mechanism of these agents. As an insulin sensitizer, metformin acts predominantly on the liver, where it suppresses glucose release (Goldfine, 2001). Metformin has also been shown to inhibit the enzymatic activity of complex I of the respiratory chain and thereby impairs both mitochondrial function and cell respiration, and in so doing decreasing the ATP/ADP ratio which activates AMP activated protein kinases causing catabolic responses on the short term and insulin sensitization on the long term (Brunmair et al., 2004; Tiikkainen et al., 2004). This drug has been proven effective in both monotherapy and in combination with sulfonylureas or insulin (Davidson and Peters, 1997). Diabetes in the young is a global phenomenon that is increasing in incidence. Some key transcription factors, important for beta-cell development, differentiation and function, are implicated in diabetes in the young. Some of these are direct targets of current therapeutic agents. The cost of current diabetic drugs is very high and the development of more affordable alternative therapies would be an advantage. The global burden of T2D is huge. Strategic action is required to endure affordable diabetes treatment to improve the quality of life of those individuals affected. This is particularly true for the developing world. It is for this reason that scientists are investigating the efficacy of indigenous plant extracts in their own country.
Rooibos, (scientific name Aspalathus linearis) is a member of the legume family of plants and is used to make a tisane (herbal tea). Aspalathus linearis is a unique South-African fynbos plant cultivated for the production of Rooibos tea. Rooibos tea is made from the stalks and leaves of the plant, which are shredded, bruised and moistened, followed by a long period of open air oxidation (“fermentation”) and sun-drying to allow for development of the characteristic Rooibos colour and flavour. Processed plant material is then sieved and packaged as loose leaves or in tea bags. This processed material is referred to as “fermented Rooibos tea”. “Green” Rooibos tea refers to the unoxidised (“unfermented”) Rooibos plant material that is processed in such a manner as to prevent or limit oxidative changes
Health-promoting properties associated with Rooibos tea include relief of insomnia, nervous tension, stomach cramps and allergic symptoms. Flavonoids in Rooibos tea have strong antioxidant and free radical scavenging activities and have the potential to act as anti-carcinogenic and anti-arteriosclerotic agents. Rooibos tea and products derived therefrom are valuable for use in food/nutraceutical, pharmaceutical and/or cosmetic industry.
At present, Type 1 diabetic patients are treated with insulin, while the majority of Type 2 diabetic patients are treated with hypoglycemic agents, such as sulfonylureas that stimulate β-cell function, with other agents that enhance the tissue selectivity of the patients towards insulin, or with insulin itself. Unfortunately, the use of insulin currently requires multiple daily doses, normally administered by self-injection, with determination of the proper dosage of insulin requiring frequent estimations of the sugar in urine or blood, performed either by the patient or the administering physician. The unintended administration of an excess dose of insulin can result in hypoglycemia, with adverse effects ranging from mild abnormalities in blood glucose to coma, or even death. Although hypoglycemic agents such as sulfonylureas have been employed widely in the treatment of NIDDM, this treatment is, in many instances, not completely satisfactory. Where existing treatments prove ineffective in normalizing blood sugar levels of patients, there is an increased risk of acquiring diabetic complications. Also, many patients gradually lose the ability to respond to treatment with sulfonylureas and are thus gradually forced into insulin treatment. Since many extant forms of diabetic therapy have proven ineffective achieving satisfactory glycemic control, there continues to be a great demand for novel therapeutic approaches.
As a result of its adipogenic effect, insulin has the undesirable effect of promoting obesity in patients with type 2 diabetes. (See, Moller, D. E. (2001) Nature 414:821-827). Unfortunately, other anti-diabetic drugs, including metformin, which are currently being used to stimulate glucose transport in patients with type 2 diabetes also possess adipogenic activity. Thus while current drug therapy may provide reduction in blood sugar, it often promotes obesity. Accordingly, new compositions and methods for treating hyperglycemia are desirable. Compositions that stimulate glucose uptake without generating concomitant adipogenic side effects are especially desirable.